tbuckley/cabot-search huggingface dataset:
Molecular characteristics of advanced colorectal cancer and multi-hit <i>PIK3CA</i> mutations.
Authors: Michael Cecchini, Ethan Sokol, Neil Vasan, Dean C. Pavlick, Richard S.P. Huang, Maureen Pelletier, Mia Alyce Levy, Lajos Pusztai, Jill Lacy, Joseph Paul Eder, Janie Yue Zhang, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2022)

3535 Background: Approximately 20% of colorectal cancer (CRC) has an activating mutation in the PIK3CA oncogene. PIK3CA codes for the catalytic subunit of phosphoinositide 3-kinase alpha (PI3Kα), which ultimately activates the AKT and mammalian target of rapamycin (mTOR) pathway. The PI3Kα inhibitor alpelisib has been approved for breast cancer where a single PIK3CA activating mutation is sufficient for response. However, two activating mutations (multi-hit) in the PIK3CA allele substantially increases PI3Kα signaling compared to single hot spot mutations and results in exceptional response to PI3Kα inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in CRC to identify patients potentially susceptible to PI3K inhibitors. Methods: Tissue-based comprehensive genomic profiling (CGP) was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified, CAP (College of American Pathologists)-accredited laboratory (Foundation Medicine Inc., Cambridge, MA, USA) on all-comers during the course of routine clinical care from 2013-2021. Approval was obtained from the Western Institutional Review Board (Protocol No. 20152817). Hybrid capture was carried out for at least 324 cancer-related genes, including PIK3CA. Results: We identified 48,836 patients with advanced CRC who underwent Foundation Medicine testing and 846 (1.7%) patients with multi-hit PIK3CA mutations. Additional clinical and molecular data was available for 41,154 of these patients of which 710 (1.7%) had multi-hit PIK3CA and 7627 (19%) had any deleterious PIK3CA mutation . The local colon tumor was used for sequencing in 70% of cases and a separate site in 30% of cases. Patients with PIK3CA multi-hit mutations were 53% male with a median age of 60 (interquartile range 50-70). The microsatellite status was available for 697 of 710 patients with multi-hit PIK3CA and 123/697 (18%) were microsatellite instability-high. The Table outlines the genes with cooccurring mutations of &gt;10% prevalence for multi-hit PIK3CA CRC, including the clinically relevant mutations in KRAS (65%) and BRAF (13%). The four most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%) and R88Q (7.1%). The most common variant pair was E542K with E545K in 4.7% of multi-hit cases. Conclusions: Double-hit mutations in PIK3CA are seen in 1.7% of advanced CRC patients and may represent a subset of patients that may have enhanced sensitivity to PI3K inhibitors. Given the high prevalence of CRC in the United States and worldwide this represents a clinically meaningful prevalence of multi-hit PIK3CA. Future investigation on the clinical utility of PI3K inhibitors may be warranted in multi-hit PIK3CA CRC.[Table: see text]
Beyond Abortion: The Consequences of Overturning <i>Roe</i>
Authors: Lynn M. Paltrow, Lisa H. Harris, Mary Faith Marshall
Journal: The American Journal of Bioethics (2022)

The upcoming U.S. Supreme Court decision in Dobbs v. Jackson Women's Health Organization has the potential to eliminate or severely restrict access to legal abortion care in the United States. We address the impact that the decision could have on abortion access and its consequences beyond abortion care. We posit that an abortion ban would, in effect, mean that anyone who becomes pregnant, including those who continue a pregnancy and give birth to healthy newborns and those with pregnancy complications or adverse pregnancy outcomes will become newly vulnerable to legal surveillance, civil detentions, forced interventions, and criminal prosecution. The harms imposed by banning or severely restricting abortion access will disproportionately affect persons of color and perpetuate structural racism. We caution that focusing on Roe as a decision that only protects ending a pregnancy ignores the protection that the decision also affords people who want to continue their pregnancies. It overlooks the ways in which overturning Roe will curtail fundamental rights for all those who become pregnant and will undermine their status as full persons meriting Constitutional protections. Such a singular focus inevitably obscures the common ground that people across the ideological spectrum might inhabit to ensure the safety, health, humanity, and rights of all people who experience pregnancy.
Microfluidic T Cell Selection by Cellular Avidity
Authors: Julian F. Ashby, Julien Schmidt, Neelima KC, Armand Kurum, Caroline Koch, Alexandre Harari, Li Tang, Sam H. Au
Journal: Advanced Healthcare Materials (2022)

Abstract No T cell receptor (TCR) T cell therapies have obtained clinical approval. The lack of strategies capable of selecting and recovering potent T cell candidates may be a contributor to this. Existing protocols for selecting TCR T cell clones for cell therapies such as peptide multimer methods have provided effective measurements on TCR affinities. However, these methods lack the ability to measure the collective strength of intercellular interactions (i.e., cellular avidity) and markers of T cell activation such as immunological synapse formation. This study describes a novel microfluidic fluid shear stress‐based approach to identify and recover highly potent T cell clones based on the cellular avidity between living T cells and tumor cells. This approach is capable of probing approximately up to 10 000 T cell–tumor cell interactions per run and can recover potent T cells with up to 100% purity from mixed populations of T cells within 30 min. Markers of cytotoxicity, activation, and avidity persist when recovered high cellular avidity T cells are subsequently exposed to fresh tumor cells. These results demonstrate how microfluidic probing of cellular avidity may fast track the therapeutic T cell selection process and move the authors closer to precision cancer immunotherapy.
Analysis of the Patient-Physician Relationship, Race, and Pain Control and Physical Function Among Adults With Chronic Low Back Pain
Authors: John C. Licciardone, Sweta Ganta, Leah Goehring, Kendall Wallace, Ryan Pu
Journal: JAMA Network Open (2022)

Importance Racial and ethnic disparities in pain outcomes are widely reported in the United States. However, the impact of the patient-physician relationship on such outcomes remains unclear. Objective To determine whether the patient-physician relationship mediates the association of race with pain outcomes. Design, Setting, and Participants This cross-sectional study uses data from the Pain Registry for Epidemiological, Clinical, and Interventional Studies and Innovation, collected from April 2016 to December 2021. All registry enrollees who identified as Black or White with chronic low back pain who had a regular physician who provided pain care were included. Data were analyzed during December 2021. Exposures Participant-reported aspects of their patient-physician relationship, including physician communication, physician empathy, and satisfaction with physician encounters. Main Outcomes and Measures The primary outcomes included low back pain intensity, measured with a numerical rating scale and physical function, measured with the Roland-Morris Disability Questionnaire. Mediator variables were derived from the Communication Behavior Questionnaire, Consultation and Relational Empathy measure, and Patient Satisfaction Questionnaire. Results Among 1177 participants, the mean (SD) age was 53.5 (13.1) years, and there were 876 (74.4%) women. A total of 217 participants (18.4%) were Black, and 960 participants (81.6%) were White. The only difference between Black and White participants in the patient-physician relationship involved effective and open physician communication, which favored Black participants (mean communication score, 72.1 [95% CI, 68.8-75.4] vs 67.9 [95% CI, 66.2-69.6]; P = .03). Black participants, compared with White participants reported worse outcomes for pain intensity (mean pain score, 7.1 [95% CI, 6.8-7.3] vs 5.8 [95% CI, 5.7-6.0]; P &amp;amp;lt; .001) and back-related disability (mean disability score, 15.8 [95% CI, 15.1-16.6] vs 14.1 [95% CI, 13.8-14.5]; P &amp;amp;lt; .001). In mediation analyses that controlled for potential confounders using disease risk scores, virtually none of the associations of race with each outcome was mediated by the individual or combined factors of physician communication, physician empathy, and patient satisfaction. Similarly, no mediation was observed in sensitivity analyses that included only participants with both chronic low back pain and the same treating physician for more than 5 years. Conclusions and Relevance These findings suggest that factors other than the patient-physician relationship were important to pain disparities experienced by Black participants. Additional research on systemic factors, such as access to high-quality medical care, may be helpful in identifying more promising approaches to mitigating racial pain disparities.
Longitudinal changes in financial burden in patients with colorectal cancer treated with curative intent: Primary results of EAQ162CD.
Authors: Sheetal Mehta Kircher, Fenghai Duan, Ellen Underwood, Ilana F. Gareen, Jorean Sicks, Gelareh Sadigh, Jennifer Marie Suga, Heather Kehn, Paul Tracy Mehan, Rajesh Bajaj, David Sam Hanson, Samir Dalia, Jared David Acoba, Michael A Taylor, Lynne I. Wagner, Ruth C Carlos
Journal: Journal of Clinical Oncology (2022)

6597 Background: We prospectively assessed financial burden (FB) due to treatment costs among patients with colorectal cancer (CRC) recruited by NCI Community Oncology Research Program (NCORP) sites. Methods: Patients with newly diagnosed CRC treated with curative intent enrolled through NCORP sites and completed the FACIT Comprehensive Score for Financial Toxicity (COST) instrument at 0-, 3, 6, and 12 months. Higher COST score (range 0-44) indicates greater financial well-being. Effects of demographic, clinical, self-efficacy and safety net affiliation on FB were assessed using linear mixed modeling with compound symmetry covariance structure to account for measurement correlation from the same subject. Results: In 450 patients (mean age 61, 47% female, 84% white, 64% colon, 31% rectal) attrition was comparable across demographics, clinical variables and baseline FB. Higher COST score was linearly correlated with time. Increasing age, income less than $60,000 (vs. less than $29,999), higher self-efficacy, and higher neighborhood socioeconomic status (nSES) predicted a higher COST score; these effects were not moderated by time. Chemotherapy receipt, insurance type, and treatment at a safety net hospital did not predict COST score. Conclusions: Among those with CRC treated with curative intent in community settings, FB improves over the 12 months post diagnosis. Individual and neighborhood level social determinants of health are protective from financial fragility.[Table: see text]
LINC-08. Neuro-Oncology tumor board – one-year experience of international collaboration
Authors: Margaret Shatara, Evan Cantor, Ashley Meyer, Andrea Ogle, Kimberly Hofmann, Tammy Green, Mary Beck, Michele McHugh, Nicole Brossier, Andrew Cluster, Ali Mian, Sonika Dahiya, Zeyad M Abdelaziz, Shady Fadel, Nahla Mobark, Musa AlHarbi, Soad AlJaouni, Abrar Aljunaid, Waleed Said, Moatasem El-ayadi, Madeha Mahmoud, Abeer Al-Battashi, Imène Chabchoub, Nisreen Khalifa, Nora Dengler, Pablo Hernáiz Driever, Nicolás Rojas Del Río, Bozenna Dembowska-Bagińska, Marta Perek-Polnik, Szymon Skoczeń, Hetal Dholaria, Sumanth Nagabushan, Milena Oliveira, Angela C Hirbe, Amy E Armstrong, David Limbrick, David H Gutmann, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The management of childhood central nervous system (CNS) tumors is complex and often faces numerous challenges in low- and middle- income countries (LMICs), including delayed diagnosis and limited treatment resources. Twinning initiatives between LMICs with high- income countries are feasible and proven to be highly effective at exchanging skills and expertise to improve diagnosis, treatment and care for children with brain tumors. METHODS: A monthly multidisciplinary international pediatric neuro-oncology tumor board via zoom videoconferencing was established in January 2021. This effort is a collaboration between Washington University School of Medicine, in St. Louis, Missouri, USA and nine international sites. Given the significant contributions of this international effort, it has since grown to include 20 institutions and cancer centers from 12 countries in the Middle East, Europe, Australia and South America. RESULTS: As of January 2022, we have held 11 tumor boards, 35 cases were reviewed, and have had 320 experts attend from several specialties – neuro-oncology, neurology, neurosurgery, neuroradiology and neuropathology. A multidisciplinary team of physicians reviewed each case and recommendations were given accordingly. We also started a quarterly neurofibromatosis (NF) meeting focused to leverage the expertise of dedicated specialists in the NF center. Two NF-focused meetings took place since establishing the program, and total of five cases were discussed. CONCLUSION: Virtual videoconferencing promotes a multi-disciplinary approach for the management of pediatric CNS tumors, and it allows access for medical expertise. We anticipate the current initiative will also provide a platform for future international research collaborations and deliver the optimal medical care for neuro-oncology patients globally. Multiple potential collaborative projects are currently underway.
The prognostic role of nephrectomy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with immunotherapy according to the novel prognostic Meet-URO score: Subanalysis of the Meet-URO 15 study.
Authors: Sara Elena Rebuzzi, Alessio Signori, Giuseppe Luigi L. Banna, Sebastiano Buti, Pasquale Rescigno, Maria Gemelli, Stefano Panni, Francesco Massari, Mariella Sorarù, Matteo Santoni, Alessio Cortellini, Veronica Prati, Hector Josè Soto Parra, Francesco Atzori, Marilena Di Napoli, Orazio Caffo, Marco Messina, Franco Morelli, Giuseppe Prati, Giuseppe Fornarini
Journal: Journal of Clinical Oncology (2022)

4535 Background: Most of mRCC pts with favorable and intermediate prognosis, according to the IMDC classification, are offered a nephrectomy. However, in the immunotherapy era, the role of nephrectomy is still unclear. In the Meet-URO 15 study we reported the higher prognostic accuracy of the Meet-URO score compared to the IMDC score, by the addition of the neutrophil-to-lymphocyte ratio (NLR) and the presence of bone metastases to the IMDC score, identifying five categories with progressively worse prognosis. For this reason, we aimed to explore the prognostic impact of the previous nephrectomy (PN) on mRCC pts receiving immunotherapy and according to the Meet-URO score groups. Methods: The Meet-URO 15 study was a multicentric retrospective analysis on 571 pretreated mRCC pts receiving nivolumab. Univariable analysis of the correlation between PN and overall survival (OS) and multivariate analysis adjusted for IMDC score, therapy line, NLR and metastatic sites were performed. The interaction of PN with the Meet-URO prognostic groups was then evaluated. Results: 503/571 pts (88%) underwent PN. A reduced risk of death (HR = 0.44; 95% CI: 0.32-0.60; p&lt; 0.001) and higher mOS and OS rate were observed in pts with PN than without (mOS: 36 vs 13 monhts; 1-year-OS 72% vs 52% and 2-year-OS 57% vs 24%, respectively). The reduced risk of death for pts who underwent PN was confirmed at the multivariate analysis (HR = 0.69; 95% CI: 0.49-0.97; p= 0.032). The percentage of pts receiving PN progressively reduced through the five Meet-URO prognostic groups (PN: group 1: 98%, group 2: 95%, group 3: 84%, group 4: 79%, group 5: 59%). No significant interaction was observed between the PN and Meet-URO score when all the five groups were considered ( p= 0.17). A significant interaction was observed when the Meet-URO groups 1,2 and 3 were taken together (HR = 0.40; 95% CI: 0.25-0.63; p&lt; 0.001), highlighting the significant protective role of the PN on OS for these three groups. For the Meet-URO groups 4 and 5, the interaction was indeed not significant (HR = 0.81; 95% CI: 0.51-1.30; p= 0.39). Conclusions: PN has a favourable prognostic impact on pretreated mRCC pts receiving immunotherapy. This benefit may be limited to mRCC pts with more favorable diseases as belonging to Meet-URO prognostic groups 1, 2 and 3. Further analysis of the type of PN (i.e., radical vs cytoreductive) is ongoing and confirmatory prospective evaluations are warranted.
Durvalumab treatment initiation delays in patients with unresectable stage III non–small cell lung cancer treated at Veterans Health Administration facilities.
Authors: Paromita Datta, Amanda Moore, Christopher R Frei, Kelly R Reveles, Lance Brannman, Ion Cotarla, Andrew Frankart, Tiernan Mulrooney, Munaf Alkadimi, Jennifer Whitehead, Kathleen Franklin, Renee Reichelderfer, Madison H. Williams, Ryan A. Williams, Sarah Allison Smith, Xavier Jones, Zohra Nooruddin
Journal: Journal of Clinical Oncology (2022)

8556 Background: Durvalumab is an FDA-approved immunotherapy for the treatment of adults with UnResectable stage III non-small cell lung cancer (UR-NSCLC) without disease progression following concurrent chemoradiotherapy (CRT). There are limited real-world data regarding Durvalumab treatment initiation delays (TIDs) and reasons for them in the UR-NSCLC population. Methods: Patients with stage III UR-NSCLC receiving consolidation Durvalumab at the Veterans Health Administration (VHA) between January 1, 2017 and June 30, 2020 were selected from the VHA database using ICD-10, HCPCS, and J codes. All had the opportunity to be treated for 12 months and were followed from Durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or the study’s end (and excluded if Durvalumab therapy was ongoing at the study’s end). Trained data abstractors determined the occurrence and reasons for TIDs (&gt; 6 weeks from end of CRT to initiation of Durvalumab as in the PACIFIC trial) by chart review. Results: 935 patients were eligible for analysis (median age = 69 years; 95% males; 16% with ECOG performance status &gt;1). TIDs occurred in 39% of the patients (Table). Durvalumab was initiated 61 days (median) from the end of CRT in TID patients vs. 31 days for those without TIDs. There were no significant (α&lt;0.05) differences in age, race, smoking status, histology, or ECOG performance status and no comorbidity differences (except in patients with a history of cerebrovascular accident, for whom TIDs were more likely) between the TID/No-TID patients. Patients without timely post-CRT scans were more likely to have a TID. Of the 367 patients who experienced TIDs, 200 had documented reasons for the delay, consisting of other (not categorized) (28.5%), physician preference (20%), toxicity (11%), patient preference (10.5%), decline in performance status (10%), system issues (9.5%), social reasons (9%), and progression (0.5%). Conclusions: This is one of the largest retrospective cohort studies reporting real-world data in patients with UR-NSCLC receiving Durvalumab. TIDs were associated with increased time to post-CRT scans. This potential issue can be improved with care coordination and involvement of cancer navigators. Additional studies are needed to assess the impact of TIDs on survival outcomes.[Table: see text]
Anti-PD1, capecitabine, and oxaliplatin for the first-line treatment of dMMR esophagogastric cancer (AuspiCiOus-dMMR): A proof-of-principle study (AuspiCiOus).
Authors: Joris Bos, Nadia Haj Mohammad, Sarah Derks, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2022)

TPS4163 Background: Doublet cytotoxic treatment demonstrates survival benefit over single drug therapies in patients with advanced esophagogastric cancer (EGC). Previous clinical data suggests an improved survival outcome in patients with microsatellite instability (MSI) treated with PD-1 inhibitor monotherapy or in combination with chemotherapy in first line palliative treatment. The positive effect of immunotherapy was only seen after a couple of months of treatment. This suggests that the patient might benefit from a short course of chemotherapy at the start of treatment. However, reports on the effects of cytotoxic treatment in MSI-high tumors range from beneficial to detrimental. Thus, the value of cytotoxic treatment, as well as the effect on the tumor immune microenvironment (TME) in MSI-high tumors is unclear. Therefore, in AuspiCious-dMMR we will study the effect of sequential treatment in patients with mismatch repair deficient (dMMR) EGC on the tumor immune microenvironment and, more specifically, the impact on the infiltration of cytotoxic T cells, before and after a short course of chemotherapy, and during treatment with PD-1 inhibition. Methods: AuspiCiOus is a multi-center, open-label, single arm (phase 2) study in patients with dMMR irresectable or metastatic EGC adenocarcinoma (NCT05177133). Patients are treated with Capecitabine and Oxaliplatin for two 3-weekly cycles, after which treatment is continued with retifanlimab (PD-1 inhibitor) for 4-weekly cycles up to progression or unacceptable toxicity, with a maximum of two years. Before treatment, after chemotherapy and after two cycles of immunotherapy fresh tumor biopsies are collected to study the primary outcome (T cell infiltration and the interferon-γ signature) as well as for translational research purposes (flow cytometry, nanostring profiling, (multicolor) immunohistochemistry and organoid culturing). Blood is collected at the same time points and on day 3 after the first course of immunotherapy for isolation of peripheral blood mononuclear cell, and determination of cytokine/chemokine profile, circulating stromal markers, and circulating tumor DNA. Also, fecal samples are collected to determine changes in the intestinal microbiome and patient reported outcome measures are used to determine quality of life. (s)AEs are assessed according to CTCAE v5 and tumor response is determined according to (i)RECIST 1.1. Key eligibility criteria are 1) histological confirmed diagnosis of untreated metastatic or irresectable HER2- adenocarcinoma of stomach or junction and 2) dMMR determination by IHC. Study is open for inclusion and three of planned 25 patients have been enrolled. Clinical trial information: NCT05177133.